A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas.
PURPOSE: In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-l...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2009
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| _version_ | 1797050979797958656 |
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| author | Meyer, T Gaya, A Dancey, G Stratford, MR Othman, S Sharma, S Wellsted, D Taylor, N Stirling, J Poupard, L Folkes, L Chan, P Pedley, R Chester, K Owen, K Violet, J Malaroda, A Green, A Buscombe, J Padhani, A Rustin, G Begent, R |
| author_facet | Meyer, T Gaya, A Dancey, G Stratford, MR Othman, S Sharma, S Wellsted, D Taylor, N Stirling, J Poupard, L Folkes, L Chan, P Pedley, R Chester, K Owen, K Violet, J Malaroda, A Green, A Buscombe, J Padhani, A Rustin, G Begent, R |
| author_sort | Meyer, T |
| collection | OXFORD |
| description | PURPOSE: In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. EXPERIMENTAL DESIGN: Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks. RESULTS: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. CONCLUSIONS: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy. |
| first_indexed | 2024-03-06T18:13:15Z |
| format | Journal article |
| id | oxford-uuid:03bc90af-a61a-4d0e-8bd3-0374177a2972 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:13:15Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:03bc90af-a61a-4d0e-8bd3-0374177a29722022-03-26T08:48:06ZA phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:03bc90af-a61a-4d0e-8bd3-0374177a2972EnglishSymplectic Elements at Oxford2009Meyer, TGaya, ADancey, GStratford, MROthman, SSharma, SWellsted, DTaylor, NStirling, JPoupard, LFolkes, LChan, PPedley, RChester, KOwen, KViolet, JMalaroda, AGreen, ABuscombe, JPadhani, ARustin, GBegent, R PURPOSE: In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. EXPERIMENTAL DESIGN: Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks. RESULTS: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. CONCLUSIONS: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy. |
| spellingShingle | Meyer, T Gaya, A Dancey, G Stratford, MR Othman, S Sharma, S Wellsted, D Taylor, N Stirling, J Poupard, L Folkes, L Chan, P Pedley, R Chester, K Owen, K Violet, J Malaroda, A Green, A Buscombe, J Padhani, A Rustin, G Begent, R A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas. |
| title | A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas. |
| title_full | A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas. |
| title_fullStr | A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas. |
| title_full_unstemmed | A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas. |
| title_short | A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas. |
| title_sort | phase i trial of radioimmunotherapy with 131i a5b7 anti cea antibody in combination with combretastatin a4 phosphate in advanced gastrointestinal carcinomas |
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